This invention relates to the fields of pharmaceutical and organic chemistry and provides novel benzo[b]thiophene compounds which are useful for the treatment and prevention of various medical indications associated with estrogen deprivation, postmenopausal syndrome, estrogen-dependent cancer, uterine fibroid disease, endometriosis, and arterial smooth muscle cell proliferation, also known as restenosis.
xe2x80x9cPostmenopausal syndromexe2x80x9d is a term used to describe various pathological conditions which frequently affect women who have entered into or completed the physiological metamorphosis known as menopause. Numerous pathologies are contemplated by the use of this term, with major effects of postmenopausal syndrome including but not limited to osteoporosis, cardiovascular effects such as hyperlipidemia, and estrogen-dependent cancer, particularly breast and uterine cancer.
Osteoporosis describes a group of diseases which arises from diverse etiologies, but which are characterized by the net loss of bone mass per unit volume. The consequence of this loss of bone mass and resulting bone fracture is the failure of the skeleton to provide adequate support for the body. One of the most common types of osteoporosis is associated with menopause. Most women lose from about 20% to about 60% of the bone mass in the trabecular compartment of the bone within 3 to 6 years after the cessation of menses. This rapid loss is generally associated with an increase of bone resorption and formation. However, the resorptive cycle is more dominant and the result is a net loss of bone mass. Osteoporosis is a common and serious disease among postmenopausal women.
There are an estimated 25 million women in the United States alone who are afflicted with this disease. The results of osteoporosis are personally harmful, and also account for a large economic loss due to its chronicity and the need for extensive and long term support (hospitalization and nursing home care) from the disease sequelae. This is especially true in more elderly patients. Additionally, although osteoporosis is generally not thought of as a life threatening condition, a 20% to 30% mortality rate is related to hip fractures in elderly women. A large percentage of this mortality rate can be directly associated with postmenopausal osteoporosis.
The most vulnerable tissue in the bone to the effects of postmenopausal osteoporosis is the trabecular bone. This tissue is often referred to as spongy or cancellous bone and is particularly concentrated near the ends of the bone (near the joints) and in the vertebrae of the spine. The trabecular tissue is characterized by small osteoid structures which interconnect with each other, as well as the more solid and dense cortical tissue which makes up the outer surface and central shaft of the bone. This interconnected network of trabeculae gives lateral support to the outer cortical structure and is critical to the biomechanical strength of the overall structure. In postmenopausal osteoporosis, it is primarily the net resorption and loss of the trabeculae which leads to the failure and fracture of bone. In light of the loss of the trabeculae in the postmenopausal woman, it is not surprising that the most common fractures are those associated with bones which are highly dependent on trabecular support, for example, the vertebrae, the neck of the weight-bearing bones such as the femur and the fore-arm. Indeed, hip fracture, collies fractures, and vertebral crush fractures are hallmarks of postmenopausal osteoporosis.
The most generally accepted method for the treatment of postmenopausal osteoporosis is estrogen replacement therapy. Although therapy is generally successful, patient compliance with the therapy is low, primarily because estrogen treatment frequently produces undesirable side effects. An additional method of treatment would be the administration of a bisphosphonate compound, such as, for example, Fosamax(copyright) (Merck and Co., Inc.).
Throughout premenopausal time, most women have less incidence of cardiovascular disease than men of the same age. Following menopause, however, the rate of cardiovascular disease in women slowly increases to match the rate seen in men. This loss of protection has been linked to the loss of estrogen and, in particular, to the loss of estrogen""s ability to regulate the levels of serum lipids. The nature of estrogen""s ability to regulate serum lipids is not well understood, but evidence to date indicates that estrogen can up regulate the low density lipid (LDL) receptors in the liver to remove excess cholesterol. Additionally, estrogen appears to have some effect on the biosynthesis of cholesterol, and other beneficial effects on cardiovascular health.
It has been reported in the literature that serum lipid levels in postmenopausal women having estrogen replacement therapy return to concentrations found in the premenopausal state. Thus, estrogen would appear to be a reasonable treatment for this condition. However, the side effects of estrogen replacement therapy are not acceptable to many women, thus limiting the use of this therapy. An, ideal therapy for this condition would be an agent which regulates serum lipid levels in a manner analogous to estrogen, but which is devoid of the side effects and risks associated with estrogen therapy.
In response to the clear need for new pharmaceutical agents which are capable of alleviating the symptoms of, inter alia, postmenopausal syndrome, the present invention provides benzo[b]thiophene compounds, pharmaceutical formulations thereof, and methods of using such compounds for the treatment of postmenopausal syndrome and other estrogen-related pathological conditions such as those mentioned below.
Another major estrogen associated pathology is estrogen-dependent breast cancer and, to a lesser extent, estrogen-dependent cancers of other organs, particularly the uterus. Although such neoplasms are not solely limited to a postmenopausal woman, they are more prevalent in the older, postmenopausal population. Current chemotherapy of these cancers have relied heavily on the use of anti-estrogen compounds, such as tamoxifene. Although such mixed agonist-antagonists have beneficial effects in the treatment of these cancers, and the estrogenic side-effects are tolerable in acute life-threatening situations, they are not ideal. For example, these agents may have stimulatory effects on certain cancer cell populations in the uterus due to their estrogenic (agonist) properties and they may, therefore, be counterproductive in some cases. A better therapy for the treatment of these cancers would be an agent which is an antiestrogenic compound having fewer or no estrogen agonist properties on reproductive tissues.
Uterine fibrosis (uterine fibroid disease) is a clinical problem which goes under a variety of names, including uterine hypertrophy, fibrosis uteri, and uterine lieomyomata, myometrial hypertrophy, and uterine metritis. Essentially, uterine fibrosis is a condition where there is an inappropriate deposition of fibroid tissue on the wall of the uterus.
This condition is a cause of dysmenorrhea and infertility in women. The exact cause of this condition is poorly understood, but evidence suggests that it is an inappropriate response of fibroid tissue to estrogen. Such a condition has been produced in rabbits by daily administrations of estrogen for three months. In guinea pigs, the condition has been produced by daily administration of estrogen for four months. In rats, estrogen causes similar hypertrophy.
The most common treatment of uterine fibrosis involves surgical procedures both costly and sometimes a source of complications due to the formation of abdominal adhesions and infection. In some patients, initial surgery is only a temporary treatment and the fibroids regrow. In those cases a hysterectomy is performed which effectively ends the fibroids but also the reproductive life of the patient. Also, gonadotropin-releasing hormone antagonists may be administered, yet their use is tempered by the fact that they can lead to osteoporosis. Thus, there exists a need for new methods for treating uterine fibrosis, and the methods of the present invention satisfy that need.
Endometriosis is a condition of severe dysmenorrhea, which is accompanied by severe pain, bleeding into the endometrial masses or peritoneal cavity, and often leads to infertility. The cause of the symptoms of this condition appear to be ectopic endometrial growths which respond to normal hormonal control (cycling), but are located in inappropriate tissues. Because of the inappropriate locations for endometrial growth, the tissues seem to initiate local inflammatory responses causing macrophage infiltration and a cascade of events leading to a painful response. The exact etiology of this disease is not well understood and its treatment by hormonal therapy is diverse, poorly defined, and marked by numerous unwanted and perhaps dangerous side effects.
One of the treatments for this disease is the use of low dose estrogen to suppress endometrial growth through a negative feedback effect on central gonadotropin release and subsequent ovarian production of estrogen. However, it is sometimes necessary to use estrogen continuously to control the symptoms. This use of estrogen can often lead to undesirable side effects and even to the risk of endometrial cancer.
Another treatment consists of continuous administration of progestins which induces amenorrhea by suppressing ovarian estrogen production, but can cause regressions of the endometrial growths. The use of chronic progestin therapy is often accompanied by the unpleasant CNS side effects of progestins, and often leads to infertility due to suppression of ovarian function.
A third treatment consists of the administration of weak androgens, which are effective in controlling the endometriosis. However, they also induce severe masculinization. Continued use of several of these treatments for endometriosis have also been implicated in mild bone loss. Therefore, new methods of treating endometriosis are desirable.
Smooth muscle cell proliferation plays an important role in diseases such as atherosclerosis and restenosis. Vascular restenosis after percutaneous transluminal coronary angioplasty (PTCA) has been shown to be a tissue response characterized by an early and a late phase. The early phase occurring hours to days after PTCA is due to thrombosis with some vasospasms, while the late phase appears to be dominated by excessive proliferation and migration of vascular aortal smooth muscle cells. In this disease, the increased cell motility and colonization by such muscle cells and macrophages contribute significantly to the pathogenesis of the disease. The excessive proliferation and migration of vascular aortal smooth muscle cells may be the primary mechanism of the reocclusion of coronary arteries following PTCA, laser angioplasty, and arterial bypass graft surgery. (See: xe2x80x9cIntimal Proliferation of Smooth Muscle Cells as an Explanation for Recurrent Coronary Artery Stenosis after Percutaneous Transluminal Coronary Angioplastyxe2x80x9d, Austin et al., Journal of the American College of Cardiology, 8: 369-375 (August 1985)).
Vascular restenosis remains a major long term complication following surgical intervention of blocked arteries by PTCA, atherectomy, laser angioplasty, and arterial bypass graft surgery. In about 35% of the patients who undergo PTCA, reocclusion occurs within three to six months after the procedure. The current strategies for treating vascular restenosis include mechanical intervention by devices such as agents or pharmacologic therapies including heparin, low molecular weight heparin, coumarin, aspirin, fish oil, calcium antagonists, steroids, and prostacyclin. These strategies have failed to curb the reocclusion rate and have been ineffective for the treatment and prevention of vascular restenosis. (See: xe2x80x9cPrevention of Restenosis after Percutaneous Transluminal Coronary Angioplasty: The Search for a xe2x80x98Magic Bulletxe2x80x99xe2x80x9d, Hermans et al., American Heart Journal, 122: 171-187 (July 1991)).
In the pathogenesis of restenosis, excessive cell proliferation and migration occurs as a result of growth factors produced by cellular constituents in the blood and in the damaged arterial vessel wall which mediate the proliferation of smooth muscle cells in vascular restenosis. Agents that inhibit the proliferation and/or migration of smooth aortal muscle cells are useful in the treatment and prevention of restenosis. The present invention provides for the use of these compounds as smooth aortal muscle cell proliferation inhibitors and thus, as inhibitors of restenosis.
Thus, it would be a significant contribution to the art to provide novel benzothiophene compounds useful, for example, in the treatment or prevention of the disease states as indicated herein.
The present invention provides compounds of formula I: 
wherein:
R1 is xe2x80x94H, xe2x80x94OH, xe2x80x94O(C1-C4 alkyl), xe2x80x94Oxe2x80x94COxe2x80x94(C1-C6 alkyl), xe2x80x94Oxe2x80x94COxe2x80x94O(C1-C6 alkyl), xe2x80x94Oxe2x80x94COxe2x80x94Ar in which Ar is optionally substituted phenyl, or xe2x80x94Oxe2x80x94SO2xe2x80x94(C4-C6 alkyl);
R2 is xe2x80x94H, xe2x80x94OH, xe2x80x94O(C1-C4 alkyl), xe2x80x94Oxe2x80x94COxe2x80x94(C1-C6 alkyl), xe2x80x94Oxe2x80x94COxe2x80x94O(C1-C6 alkyl), xe2x80x94Oxe2x80x94COxe2x80x94Ar in which Ar is optionally substituted phenyl, xe2x80x94Oxe2x80x94SO2xe2x80x94(C4-C6 alkyl), xe2x80x94F, xe2x80x94Cl, or xe2x80x94Br;
n is an integer from 3 to 8;
R3 and R4 each are independently C1-C4 alkyl, or combine to form, with the nitrogen to which they are attached, piperidinyl, pyrrolidinyl, methylpyrrolidinyl, dimethylpyrrolidinyl, or hexamethyleneimino;
with the proviso that when n is 3, then R1 and R2 cannot be xe2x80x94Oxe2x80x94SO2xe2x80x94(C4-C6 alkyl); or a pharmaceutically acceptable salt or solvate thereof.
The present invention further provides pharmaceutical formulations containing compounds of formula I, optionally containing an effective amount of an additional therapeutic agent selected from the group consisting of estrogen, progestin, bisphosphonate, PTH, and subcombinations thereof, and the use of said compounds and/or subcombinations at least for the treatment of estrogen deprivation, postmenopausal symptoms, particularly osteoporosis, cardiovascular-related pathological conditions including hyperlipidemia and related cardiovascular pathologies, and estrogen-dependent cancer.
The present invention still further provides pharmaceutically acceptable compositions comprising a compound of formula I and optionally additional therapeutic agents, along with pharmaceutically acceptable diluents or carriers.
The present invention also provides methods of use of the compounds of formula I for the treatment of uterine fibrosis and endometriosis in women, and for the inhibition of aortal smooth muscle cell proliferation and restenosis in humans.
The present invention additionally provides processes for the synthesis of the novel compounds, as well as intermediates therefor.
General terms used in the description of compounds herein described bear their usual meanings. For example, xe2x80x9cC1-C4 alkylxe2x80x9d refers to straight or branched aliphatic chains of 1 to 4 carbon atoms including methyl, ethyl, propyl, iso-propyl, n-butyl, and the like; and xe2x80x9cC1-C6 alkylxe2x80x9d encompasses the groups included in the definition of xe2x80x9cC1-C4 alkylxe2x80x9d in addition to groups such as pentyl, iso-pentyl, hexyl, and the like.
The term xe2x80x9csubstituted phenylxe2x80x9d refers to a phenyl group having one or more substituents selected from the group consisting of C1-C4 alkyl, C1-C3 alkoxy, hydroxy, nitro, chloro, fluoro, tri(chloro or fluoro)methyl, and the like. xe2x80x9cC1-C4 alkoxyxe2x80x9d refers to a C1-C4 alkyl group attached through an oxygen bridge, such as methoxy, ethoxy, n-propoxy, and isopropoxy, butoxy, and the like. Of these C1-C4 alkoxy groups, methoxy is highly preferred.
Preferred embodiments of the present invention are those compounds wherein n is an integer from 4 to 8. Especially preferred are those compounds wherein n is 5 to 8. Particularly preferred are those compounds wherein n is 5 to 8, R1 and R2 are hydroxy, and R3 and R4, together with the nitrogen to which they are attached, form a pyrrolidine, piperidine, or hexamethyleneimino ring, and their hydrochloride salts.
Preferred compounds are those selected from the group consisting of
[2-(4-Methoxyphenyl)-6-methoxybenzo[b]thien-3-yl][4-(8-bromo-octyloxy)phenyl]methanone,
[2-(4-Methoxyphenyl)-6-methoxybenzo[b]thien-3-yl][4-(7-bromo-heptyloxy)phenyl]methanone,
[2-(4-Methoxyphenyl)-6-methoxybenzo[b]thien-3-yl][4-(6-bromo-hexyloxy)phenyl]methanone,
[2-(4-Methoxyphenyl)-6-methoxybenzo[b]thien-3-yl][4-(5-bromo-pentyloxy)phenyl]methanone,
[2-(4-Methoxyphenyl)-6-methoxybenzo[b]thien-3-yl][4-(4-bromo-butyloxy)phenyl]methanone,
[2-(4-Methoxyphenyl)-6-methoxybenzo[b]thien-3-yl][4-(3-bromo-propyloxy)phenyl]methanone,
[2-(4-Methoxyphenyl)-6-methoxybenzo[b]thien-3-yl][4-[8-(1-pyrrolidinyl)octyloxyl]phenyl]methanone,
[2-(4-Methoxyphenyl)-6-methoxybenzo[b]thien-3-yl][4-[7-(1-pyrrolidinyl)heptyloxyl]phenyl]methanone,
[2-(4-Methoxyphenyl)-6-methoxybenzo[b]thien-3-yl][4-[6-(1-pyrrolidinyl)hexyloxyl]phenyl]methanone,
[2-(4-Methoxyphenyl)-6-methoxybenzo[b]thien-3-yl][4-[5-(1-pyrrolidinyl)pentyloxyl]phenyl]methanone,
[2-(4-Methoxyphenyl)-6-methoxybenzo[b]thien-3-yl][4-[4-(1-pyrrolidinyl)butyloxyl]phenyl]methanone,
[2-(4-Methoxyphenyl)-6-methoxybenzo[b]thien-3-yl][4-[3-(1-pyrrolidinyl)propyloxyl]phenyl]methanone,
[2-(4-Hydroxyphenyl)-6-hydroxybenzo[b]thien-3-yl][4-[8-(1-pyrrolidinyl)octyloxyl]phenyl]methanone,
[2-(4-Hydroxyphenyl)-6-hydroxybenzo[b]thien-3-yl][4-[7-(1-pyrrolidinyl)heptyloxyl]phenyl]methanone,
[2-(4-Hydroxyphenyl)-6-hydroxybenzo[b]thien-3-yl][4-[6-(1-pyrrolidinyl)hexyloxyl]phenyl]methanone,
[2-(4-Hydroxyphenyl)-6-hydroxybenzo[b]thien-3-yl][4-[5-(1-pyrrolidinyl)pentyloxyl]phenyl]methanone,
[2-(4-Hydroxyphenyl)-6-hydroxybenzo[b]thien-3-yl][4-[4-(1-pyrrolidinyl)butyloxyl]phenyl]methanone, and
[2-(4-Hydroxyphenyl)-6-hydroxybenzo[b]thien-3-yl][4-[3-(1-pyrrolidinyl)propyloxyl]phenyl]methanone.
The compounds of this invention are derivatives of benzo[b]thiophene, which are named and numbered according to the Ring Index, The American Chemical Society, as follows: 
The compounds of the present invention, for example, compounds of formula I, may be synthesized essentially as described in U.S. Pat. Nos. 4,133,814, 4,358,593, 4,418,068, 5,393,763, and 5,482,949, the disclosure of which is herein incorporated by reference.
Generally, a benzothiophene precursor of formula II may be prepared by procedures known in the art. 
(wherein R1 and R2 are as previously defined.) 
(wherein n, R3, and R4 are as previously defined.)
Following preparation of the desired precursor, compounds of formula II may be acylated at the 3-position of the benzothiophene nucleus with activated carboxyl moieties of the compounds of formula III under standard Friedel-Crafts conditions. In general, the acylating conditions would be the use of a Lewis acid, such as AlCl3, BF3, and the like, in an appropriate solvent, such as a halogenated hydrocarbon, at temperatures from 0-100xc2x0 C. The activated carboxyl moieties of the compounds of formula III are acyl halides, mixed anhydrides, and the like, with the preferred being the acid chloride. The compounds of formula II may be prepared in accordance with the methods described in U.S. Pat. No. 4,133,814. It would be understood to those skilled in the art of organic chemistry that the ligands R1 and R2 must be compatible with the acylating conditions to form the compounds of formula I, thus a preferred intermediate would be where R1 and R2 are xe2x80x94OMe. The activated carboxyls of the compounds of formula III may be prepared from commercially available carboxylic acids by methods known in the art, with agents such as thionyl chloride.
A more preferred method of preparing the compounds of formula I would be to acylate the 3-position on a compound of formula II with 4-methoxybenzoyl chloride, using standard Friedel-Crafts conditions, to form the compounds of formula IV. 
(wherein R1 and R2 are as previously defined, and R5 is xe2x80x94H or xe2x80x94CH3.)
This method is preferred due to the lability of the O-alkyl side chain in the presence of Friedel-Crafts conditions (for example, in the presence of strong Lewis acids, the longer O-alkyl chains are partially cleaved). The 4-OMe group of the benzoyl moiety may be selectively removed using NaSEt to form the compounds of formula IV as the phenol. The phenolic compounds of formula IV may O-alkylated with the compounds of formula V using an inorganic base such as K2CO3, Ca2CO3, and the like, to form the final compounds of formula I.
(Cl)Brxe2x80x94(CH2)nxe2x80x94NR3R4xe2x80x83xe2x80x83V
(wherein n, R3, and R4 are as previously defined.)
An alternative and also preferred method to synthesize the compounds of formula I is to O-alkylate the phenolic compounds of formula IV with di-halo alkanes to form the compounds of formula VI. 
(wherein R1, R2, and n are as previously defined.)
The preferred di-halo alkanes would be the di-bromo moieties. The bromine in the compounds of formula VI may be displaced with the appropriate amine or amines to form the compounds of formula I. Other derivatives such as hydroxyls or esters derived from them may be obtained by cleaving the methoxy protecting groups. Care must be taken in this cleavage procedure not to cleave O-alkyl basic side chain. Standard methods of methoxy cleavage such as AlCl3 by itself, cleaves the basic side-chain. This problem may be circumvented by using a combination of AlCl3 and NaSEt. Ester derivatives may be obtained from the hydroxy compounds by methods known in the art.
Although the free-base form of formula I compounds can be used in the methods of the present invention, it is preferred to prepare and use a pharmaceutically acceptable salt form. The term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d refers to either acid or base addition salts which are known to be non-toxic and are commonly used in the pharmaceutical literature. The pharmaceutically acceptable salts generally have enhanced solubility characteristics compared to the compound from which they are derived, and thus are often more amenable to formulation as liquids or emulsions. The compounds used in the methods of this invention primarily form pharmaceutically acceptable acid addition salts with a wide variety of organic and inorganic acids, and include the physiologically acceptable salts which are often used in pharmaceutical chemistry. Such salts are also part of this invention. Typical inorganic acids used to form such salts include hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric, and the like. Salts derived from organic acids, such as aliphatic mono and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic and hydroxyalkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, may also be used. Such pharmaceutically acceptable salts thus include acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate, xcex2-hydroxybutyrate, butyne-1,4-dioate, hexyne-1,4-dioate, caproate, caprylate, chloride, cinnamate, citrate, formate, fumarate, glycolate, heptanoate, hippurate, lactate, malate, maleate, hydroxymaleate, malonate, mandelate, mesylate, nicotinate, isonicotinate, nitrate, oxalate, phthalate, terephthalate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, propiolate, propionate, phenylpropionate, salicylate, sebacate, succinate, suberate, sulfate, bisulfate, pyrosulfate, sulfite, bisulfite, sulfonate, benzenesulfonate, p-bromophenylsulfonate, chlorobenzenesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, methanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, p-toluenesulfonate, xylenesulfonate, tartarate, and the like. A preferred salt is the hydrochloride salt.
The pharmaceutically acceptable acid addition salts are typically formed by reacting a compound of formula I with an equimolar or excess amount of acid. The reactants are generally combined in a mutual solvent such as diethyl ether or ethyl acetate. The salt normally precipitates out of solution within about one hour to 10 days and can be isolated by filtration, or the solvent can be stripped off by conventional means.
Further, the present invention provides for pharmaceutically acceptable formulations for administering to a mammal, including humans, in need of treatment, which comprises an effective amount of a compound of formula I and a pharmaceutically acceptable diluent or carrier.
As used herein, the term xe2x80x9ceffective amountxe2x80x9d means an amount of compound of the present invention which is capable of inhibiting, alleviating, ameliorating, treating, or preventing further symptoms in mammals, including humans, suffering from estrogen deprivation, for example, menopause or ovariectomy, or inappropriate estrogen stimulation such as uterine fibrosis or endometriosis, or suffering from aortal smooth muscle cell profileration or restenosis. In the case of estrogen-dependent cancers, the term xe2x80x9ceffective amountxe2x80x9d means the amount of compound of the present invention which is capable of alleviating, ameliorating, inhibiting cancer growth, treating, or preventing the cancer and/or its symptoms in mammals, including humans.
By xe2x80x9cpharmaceutically acceptable formulationxe2x80x9d it is meant that the carrier, diluent, excipients and salt must be compatible with the active ingredient (a compound of formula I) of the formulation, and not be deleterious to the recipient thereof.
Pharmaceutical formulations can be prepared by procedures known in the art. For example, the compounds of this invention can be formulated with common excipients, diluents, or carriers, and formed into tablets, capsules, and the like. Examples of excipients, diluents, and carriers that are suitable for such formulations include the following: fillers and extenders such as starch, sugars, mannitol, and silicic derivatives; binding agents such as carboxymethyl cellulose and other cellulose derivatives, alginates, gelatin, and polyvinyl pyrrolidone; moisturizing agents such as glycerol; disintegrating agents such as agar agar, calcium carbonate, and sodium bicarbonate; agents for retarding dissolution such as paraffin; resorption accelerators such as quaternary ammonium compounds; surface active agents such as cetyl alcohol, glycerol monostearate; adsorptive carriers such as kaolin and bentonite; and lubricants such as talc, calcium and magnesium stearate and solid polyethylene glycols. Final pharmaceutical forms may be: pills, tablets, powders, lozenges, syrups, aerosols, saches, cachets, elixirs, suspensions, emulsions, ointments, suppositories, sterile injectable solutions, or sterile packaged powders, and the like, depending on the type of excipient used.
Additionally, the compounds of this invention are well suited to formulation as sustained release dosage forms. The formulations can also be so constituted that they release the active ingredient only or preferably in a particular part of the intestinal tract, possibly over a period of time. Such formulations would involve coatings, envelopes, or protective matrices which may be made from polymeric substances or waxes.
The particular dosage of a compound of formula I required to treat, inhibit, or prevent the symptoms and/or disease of a mammal, including humans, suffering from the above maladies according to this invention will depend upon S the particular disease, symptoms, and severity. Dosage, routes of administration, and frequency of dosing is best decided by the attending physician. Generally, accepted and effective doses will be from 50 mg to 1000 mg, and more typically from 80 mg and 500 mg. Such dosages will be administered to a patient in need of treatment from one to three times each day or as often as needed for efficacy.
As a further embodiment of the invention, the compounds of formula I may be administered along with an effective amount of an additional therapeutic agent, including but not limited to estrogen, progestin, other benzothiophene compounds including raloxifene, bisphosphonate compounds such as alendronate and tiludronate, parathyroid hormone (PTH), including truncated and/or recombinant forms of PTH such as, for example, PTH 1-34, calcitonin, bone morphogenic proteins (BMPs), or combinations thereof. The different forms of these additional therapeutic agents available as well as the various utilities associated with same and the applicable dosing regimens are well known to those of skill in the art.
Various forms of estrogen and progestin are commercially available. As used herein, the term xe2x80x9cestrogenxe2x80x9d includes compounds having estrogen activity and estrogen-based agents. Estrogen compounds useful in the practice of the present invention include, for example, estradiol estrone, estriol, equilin, equilenin, estradiol cypionate, estradiol valerate, ethynyl estradiol, polyestradiol phosphate, estropipate, diethylstibestrol, dienestrol, chlorotrianisene, and mixtures thereof. Estrogen-based agents, include, for example, 17-xcex1-ethynyl estradiol (0.01-0.03 mg/day), mestranol (0.05-0.15 mg/day), and conjugated estrogenic hormones such as Premarin(copyright) (Wyeth-Ayerst; 0.2-2.5 mg/day). As used herein, the term xe2x80x9cprogestinxe2x80x9d includes compounds having progestational activity such as, for example, progesterone, norethynodrel, norgestrel, megestrol acetate, norethindrone, progestin-based agents, and the like. Progestin-based agents include, for example, medroxyprogesterone such as Provera(copyright) (Upjohn; 2.5-10 mg/day), norethylnodrel (1.0-10.0 mg/day), and norethindrone (0.5-2.0 mg/day). A preferred estrogen-based compound is Premarin(copyright), and norethylnodrel and norethindrone are preferred progestin-based agents. The method of administration of each estrogen- and progestin-based agent is consistent with that known in the art.
The formulations which follow are given for purposes of illustration and are not intended to be limiting in any way. The total active ingredients in such formulations comprises from 0.1% to 99.9% by weight of the formulation. The term xe2x80x9cactive ingredientxe2x80x9d means a compound of formula I.
The ingredients are blended, passed through a No. 45 mesh U.S. sieve, and filled into hard gelatin capsules.
The active ingredient, starch, and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a No. 14 mesh U.S. sieve. The granules thus produced are dried at 50-60xc2x0 C. and passed through a No. 18 mesh U.S. sieve. The sodium carboxymethylcellulose, magnesium stearate, and talc, previously passed through a No. 60 mesh U.S. sieve, are added to the above granules and thoroughly mixed. The resultant material is compressed in a tablet forming machine to yield the tablets.
The active ingredient is mixed with ethanol and the mixture added to a portion of the propellant 22, cooled to xe2x88x9230xc2x0 C. and transferred to a filling device. The required amount is then fed to a stainless steel container and diluted with the remainder of the propellant. The valve units are then fitted to the container.
The active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the fatty acid glycerides which had previously heated to their melting point. The mixture is poured into a suppository mold and allowed to cool.
A compound of formula I is passed through a No. 45 mesh U.S. sieve and mixed with the sodium carboxymethyl cellulose and syrup to form a smooth paste. The benzoic acid solution, flavor, and color diluted in water are added and mixture stirred thoroughly. Additional water is added to bring the formulation to final volume.